The objective of this project is to develop a commercial system for DNA sequencing using microfabricated devices that would enable whole-genome mammalian sequencing for about $100,000. "Sequencing by separation" has been the de facto method of DNA analysis since the 1970s; however current commercial systems that implement this using capillary electrophoresis are unlikely to be developed beyond the point where whole-genome sequencing will cost about $5,000,000. This project will support the development of commercial systems that will advance the price-performance of DNA separation using current, proven genome sequencing methodologies (i.e. PCR and Sanger sequencing) beyond that achievable with capillary systems. Current "assembly line" sequencing requires expensive automation and robotics, as well as the preparation of several hundred times the amount of expensive sample and reagent needed for electrophoresis. This project will eliminate the need for this by using large scale microfabrication to integrate the various component steps in a large scale biochip device. Specific microfabricated systems and sub-systems will be developed that can be deployed as direct replacements of existing components in high and medium-throughput sequencing facilities. Substantial cost reductions are expected from the integration of microscale fluid processes, leading to significant reductions in reagent consumption, and the replacement of expensive liquid-handling automation by dedicated microfluidics-based liquid-handling.